Mode of action study of antibacterial compounds for rational molecular design

2013 Fiscal Year Final Research Report

• Project/Area Number: 21310136
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Living organism molecular science
• Research Institution: Tohoku University
• Principal Investigator: ARIMOTO HIROKAZU 東北大学, 生命科学研究科, 教授 (60262789)
• Project Period (FY): 2009-04-01 – 2013-03-31
• Keywords: 抗菌性物質 / 耐性菌 / バンコマイシン

Research Abstract

Vancomycin is a clinically used antibacterial against nosocomial infections. However, vancomycin-resistant enterococci (VRE) is now widespread over the world. Moreover, the resistant nature of VRE has been transferred to Staphylococcus aureus, the major nosocomial pathogen. In this study, chemical modifications of vancomycin was conducted to restore its activity to the resistant bacteria. Three major achievements are the following. 1) Cell wall intermediates of vancomycin-resistant bacteria were chemically prepared. It made it possible to examine peptidoglycan biosynthesis in vitro greater in detail. 2) A novel vancomycin modification method using cross-coupling reaction was developed. 3) The active conformation of vancomycin dimers was experimentally suggested.

Research Products

• [Journal Article] Staphylococcus aureus Penicillin-Binding Protein 2 Can Use Depsi-Lipid II Derived from Vancomycin-Resistant Strains for Cell Wall Synthesis (2013)
  • Author(s): Nakamura, J.; Yamashiro, H.; Miya, H.; Nishiguchi, K.; Maki, H.; Arimoto, H
  • Journal Title: Chemistry - A European Journal Volume: 19 Pages: 12104-12112
  • DOI: 10.1002/chem.201301074
  • Peer Reviewed
• [Journal Article] Mapping of a Lipoglycopeptide Antibiotic Binding Site on Staphylococcus aureus Penicillin-Binding Protein 2 Using a Vancomycin Photoaffinity Analogue (2012)
  • Author(s): Nakamura, J.; Ichikawa, R.; Yamashiro, H.; Takasawa, T.; Wang, X.; Kawai, Y.; Xu, S.; Maki, H.; Arimoto, H
  • Journal Title: Medicinal Chemistry Communications Volume: 3 Pages: 691-695
  • DOI: 10.1039/C2MD20005H
  • Peer Reviewed
• [Journal Article] Elucidation of the active conformation of vancomycin dimers with antibacterial activity against vancomycin-resistant bacteria (2012)
  • Author(s): Nakamura, J.; Yamashiro, H.; Hayashi, S.; Yamamoto, M.; Miura, K.; Xu, S.; Doi, T.; Maki, H.; Yoshida, O.; Arimoto, H
  • Journal Title: Chemistry - A European Journal Volume: 18 Pages: 12681-12689
  • DOI: 10.1002/chem.201201211
  • Peer Reviewed
• [Journal Article] New Insight into the Mode of Action of Vancomycin dimers in Bacterial Cell Wall Synthesis (2011)
  • Author(s): Yoshida, O.; Nakamura, J.; Yamashiro, H.; Miura, K.; Hayashi, S.; Umetsu, K.; Xu, S.; Maki, H.; Arimoto, H
  • Journal Title: Medicinal Chemistry Communications Volume: 2 Pages: 278-282
  • DOI: 10.1039/C0MD00230E
  • Peer Reviewed
• [Journal Article] Mode of Action of Van-M-02, a Novel Glycopeptide Inhibitor of Peptidoglycan Synthesis, in Vancomycin-resistant Bacteria (2010)
  • Author(s): Miura, K.; Yamashiro, H.; Uotani, K.; Kojima, S.; Yutsudo, T.; Lu, J.; Yoshida, O.; Yamano, Y.; Maki, H.; Arimoto, H
  • Journal Title: Antimicrobial Agents and Chemotherapy Volume: 54 Pages: 960-962
  • DOI: 10.1128/AAC.00927-09
  • Peer Reviewed
• [Journal Article] Discovery of a novel series of semi-synthetic vancomycin derivatives effective against vancomycin-resistant bacteria (2010)
  • Author(s): Nakama,Y.; Yoshida,O.; Yoda, M.; Araki,K.; Sawada, Y.; Nakamura, J.; Xu, S.; Miura, K.; Maki, H.; Arimoto, H
  • Journal Title: Journal of Medicinal Chemistry Volume: 53 Pages: 2528-2533
  • DOI: 10.1021/jm9017543
  • Peer Reviewed
• [Presentation] 感染症の制御に向けた化学からのアプローチ (2012)
  • Author(s): 有本博一
  • Organizer: 中西シンポジウム2012
  • Place of Presentation: 慶応義塾大学(横浜市)
  • Year and Date: 2012-03-25
• [Presentation] 感染症の理解と制御のための化学的アプローチ (2011)
  • Author(s): 有本博一
  • Organizer: 日本化学会会員増強のための講演会
  • Place of Presentation: 東北大学理学部(仙台市)
  • Year and Date: 2011-11-25
• [Presentation] Chemical Approaches for Understanding and Controlling Infectious Diseases (2011)
  • Author(s): 有本博一
  • Organizer: The Uehara Memorial Foundation Synposium-2011 : Chembiomolecular Science : at the Frontier of Chemistry and Biology
  • Place of Presentation: Hyatt Regency Tokyo(東京都新宿区)
  • Year and Date: 2011-06-08
• [Presentation] 感染症の理解と制御のための化学的アプローチ (2011)
  • Author(s): 有本博一
  • Organizer: 第13回生命化学研究会
  • Place of Presentation: 仙台市ホテル佐勘
  • Year and Date: 2011-01-08
• [Presentation] 感染症の理解と制御のための化学的アプローチ (2010)
  • Author(s): 有本博一
  • Organizer: 神奈川大学工学部学術フロンティアプロジェクト公開シンポジウム
  • Place of Presentation: 横浜市神奈川大学横浜キャンパス
  • Year and Date: 2010-10-02
• [Presentation] 感染症の理解と制御のための化学的アプローチ (2010)
  • Author(s): 有本博一
  • Organizer: 第22回万有札幌シンポジウム
  • Place of Presentation: 札幌市さっぽろ芸術文化の館
  • Year and Date: 2010-07-03
• [Presentation] バンコマイシン耐性の理解と制御を目指した化学的アプローチ (2009)
  • Author(s): 有本博一
  • Organizer: 日本薬学会 第31回 生体膜と薬物の相互作用シンポジウム
  • Place of Presentation: 大阪大学コンベンションホール (大阪府吹田市)
  • Year and Date: 2009-11-30
• [Presentation] 感染症の理解と制御のための化学的アプローチ (2009)
  • Author(s): 有本博一
  • Organizer: 第8回 化学系薬学若手研究者セミナー
  • Place of Presentation: 東北薬科大学(宮城県仙台市)
  • Year and Date: 2009-10-03
• [Presentation] 産学連携による新規抗菌薬の探索 (2009)
  • Author(s): 有本博一
  • Organizer: 第57回 日本化学療法学会総会
  • Place of Presentation: ホテル日航東京(東京都)
  • Year and Date: 2009-06-04
• [Book] 有機合成化学協会編 : "天然物合成で活躍した反応:実験のコツとポイント" (2011)
  • Author(s): 有本博一 (分担執筆)
  • Total Pages: 224-225
  • Publisher: 化学同人
• [Remarks]
  • URL: http://www.agri.tohoku.ac.jp/bunseki/ArimotoGroup.html
• [Patent(Industrial Property Rights)] グリコペプチド抗生物質ダイマー誘導体 (2011)
  • Inventor(s): 有本博一,路軍,山野佳則,吉田修
  • Industrial Property Rights Holder: 塩野義製薬株式会社、国立大学法人名古屋大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 4888863
  • Acquisition Date: 2011-12-22